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EP0200966A2 - Méthode de stabilisation d'un précurseur d'urokinase et préparation sèche contenant ce précurseur - Google Patents

Méthode de stabilisation d'un précurseur d'urokinase et préparation sèche contenant ce précurseur Download PDF

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Publication number
EP0200966A2
EP0200966A2 EP86105235A EP86105235A EP0200966A2 EP 0200966 A2 EP0200966 A2 EP 0200966A2 EP 86105235 A EP86105235 A EP 86105235A EP 86105235 A EP86105235 A EP 86105235A EP 0200966 A2 EP0200966 A2 EP 0200966A2
Authority
EP
European Patent Office
Prior art keywords
precursor
albumin
preparation
salts
urokinase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP86105235A
Other languages
German (de)
English (en)
Other versions
EP0200966B1 (fr
EP0200966A3 (en
Inventor
Kazuo Morimoto
Shusaku Narita
Masahide Kondo
Syoichi Ishikawa
Kazuhiro Ohara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Green Cross Corp
Original Assignee
Green Cross Corp Japan
Green Cross Corp Korea
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP60079428A external-priority patent/JPS61238731A/ja
Priority claimed from JP60079429A external-priority patent/JPS61238732A/ja
Application filed by Green Cross Corp Japan, Green Cross Corp Korea filed Critical Green Cross Corp Japan
Publication of EP0200966A2 publication Critical patent/EP0200966A2/fr
Publication of EP0200966A3 publication Critical patent/EP0200966A3/en
Application granted granted Critical
Publication of EP0200966B1 publication Critical patent/EP0200966B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6456—Plasminogen activators
    • C12N9/6462—Plasminogen activators u-Plasminogen activator (3.4.21.73), i.e. urokinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21073—Serine endopeptidases (3.4.21) u-Plasminogen activator (3.4.21.73), i.e. urokinase

Definitions

  • the present invention relates to a method of stabilizing a urokinase precursor and a dry preparation containing said precursor.
  • a urokinase precursor secreted from human kidney cells does not exhibit urokinase activity by itself. However, when digested with a proteinase, such as plasmin, the precursor is transformed into a molecule which shows a high urokinase activity.
  • a proteinase such as plasmin
  • the urokinase precursor has a high affinity to fibrin and reaches the fibrin constituting a blood clot without acting on or decomposing fibrinogen in the blood plasma. Thereafter, the precursor exhibits the urokinase activity by the action of plasmin. That is, the urokinase precursor causes limited fibrin dissolution in the blood clot site and dissolves the blood clot selectively and efficiently. Therefore, the precursor is believed to be useful as a novel medicine for treatment of the disease of thrombosis.
  • the urokinase precursor is unstable in a highly purified condition, or dried or freeze dried condition, although it is relatively stable when stored in a neutral solvent in a high concentration during the processes of preliminary purification and final purification.
  • An object of the present invention is to provide a method of stabilizing a urokinase precursor and also to a dry preparation containing a stabilized urokinase precursor.
  • a dried urokinase precursor is stabilized when a mixture of (a) at least one member of inorganic salts, organic acid salts, and polar amino acids and their salts, and (b) human albumin is added to the precursor.
  • the present invention relates to a method of stabilizing a urokinase precursor by adding thereto (a) at least one member of inorganic salts, organic acid salts, and polar amino acids and their salts, and (b) alubmin.
  • the present invention relates to a dry preparation containing a stabilized urokinase precursor.
  • the urokinase precursor as used herein includes those precursors obtained from urine, human kidney cells, and by the genetic engineering (see JP-A-62981/1985 corresponding to U.S. Patent Application Serial No. 06/648,134, for example).
  • the effect of the present invention is particularly remarkable in a highly purified urokinase precursor, such as a urokinase precursor of a concentration that the specific activity is 100,000 IU/mg protein.
  • IU is an abbreviation of an international unit of UK.
  • 1 IU/ml which is equivalent to the UK activity when 1 ml of the precursor is treated with plasmin, means that 1 ml of the precursor, when treated with plasmin, has the same activity as that of 1 IU of UK.
  • Examples of the inorganic salts that are used in the present invention are alkali metal and alkaline earth metal salts of halogen, and alkali metal and alkaline earth metal salts of phosphoric acid.
  • Preferred are sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, and calcium phosphate.
  • organic acids aliphatic carboxylic acids which may have a hydroxyl group are preferably used.
  • the .number of carboxyl groups - is preferably 1 to 3 and the number of hydr-oxyl groups is preferably 0 to 3.
  • Suitable examples of these organic acids are oxy acids such as citric acid, aliphatic dicarboxylic acids such as oxalic acid, and fatty acids such as acetic acid and mandelic acid.
  • alkali metal salts examples include sodium and potassium salts.
  • Examples of the polar amino acids that are used in the present invention are glutamic acid, aspartic acid, arginine, lysine, and histidine.
  • Suitable examples of the salts of the above polar amino acids are sodium glutamate and arginine chloride.
  • organic acid salts and poler amino acids more particularly arginine and sodium citrate, are preferred.
  • the albumin as used herein is preferably albumin obtained from human in view of the problem of antigenicity.
  • the purity is preferred to be such that the albumin content as determined by electrophoresis is not less than 80%.
  • Methods of obtaining human albumin include the ethanol fractionation method (see Japanese Patent Publication N os. 2869/72 and 5297/60), and the method comprising heating in the presence of organic acids (see Japanese Patent Publication Nos. 1604/68 and 40132/76). It is particularly preferred to subject the albumin to heat treatment (preferably at 60°C for about 10 hours) for inactivation of hepatitis virus, for example.
  • Albumin is added in an amount corresponding to 10 to 60 mg, preferably 25 to 50 mg, and the inorganic salt, organic acid salt, or polar amino acid or its salt is added in an amount corresponding to 2 to 50 mg, preferably 5 to 30 mg, per 10,000 to 250,000 I U of the urokinase precursor.
  • the stabilizers of the present invention i.e., inorganic salts, organic acid salts, polar amino acids or their salts, are added with good results at any stage during the process that the urokinase precursor is placed under conditions where the precursor could be inactivated, such as the purification and storage of the urokinase precursor.
  • the activity of the urokinase precursor was measured, after activation with plasmin, by the use of a synthetic substrate (Glt-Gly-Arg-MCA).
  • a solution of a purified urokinase precursor (specific activity: 135,000 IU/mg protein) in a 0.10 M phosphate buffer (pH:6.0) as a solvent was added a solution of albumin in the same buffer as above as a solvent to prepare 25,000 IU/ml of an aqueous urokinase precursor solution containing 20 mg/ml of human albumin.
  • Various additives inorganic salts, organic acid salts, or polar amino acids or their salts
  • the aqueous urokinase precursor solution not containing any additive, and the aqueous urokinase precursor solution with only human albumin added thereto were freeze dried in the same manner as above.
  • Freeze dried preparations were prepared in the same manner as in Experiment 1 containing human albumin, sodium citrate, salt (NaCl), arginine, or sodium glutamate which rates were varied.
  • the titer shown in Tables 1 and 2 is a residual activity against the titer before the above treatment as 100.
  • 25,000 IU of a purified urokinase precursor (specific activity: 135,000 IU/mg protein), 20 mg of human albumin, and 6.4 mg of sodium citrate were dissolved in 1 ml of a 0.1 M phosphate buffer (pH, 7.0), aseptically filtered, charged in a vial bottle, and then freeze dried to prepare an injection preparation containing 25,000 units of urokinase precursor, 20 mg of human albumin and 6.4 mg of sodium citrate.
  • a preparation containing 25,000 IU of urokinase precursor, 20 mg of human albumin and 6.4 mg of table salt (NaCl) was prepared in the same manner as in Example 1.
  • 50,000 IU of a purified urokinase precursor (specific acitivity: 135,000 IU/mg protein), 40 mg of human albumin and 12.8 mg of sodium citrate were processed in the same manner as in Example 1 to prepare a preparation containing 50,000 IU of urokinase precursor, 40 mg of human albumin and 12.8 mg of sodium citrate.
  • 25,000 IU of a purified urokinase precursor (specific activity: 135,000 IU/mg protein), 20 mg of human albumin, and 6.4 mg of arginine were dissolved in 1 ml of a 0.lM phosphate buffer (pH, 7.0), aseptically filtered, charged in a vial bottle, and then freeze dried to prepare a prepation containing 25,000 IU of urokinase precursor, 20 mg of human albumin and 6.4 mg of arginine.
  • a preparation containing 25,000 IU of urokinase precursor, 20 mg of human albumin and 6.4 mg of sodium glutamate was prepared in the same manner as in Example 1.
  • 50,000 IU of a purified urokinase precursor (specific activity: 135,000 IU/mg protein), 40 mg of human albumin and 12.8 mg of arginine were processed in the same manner as in Example 1 to prepare a preparation containing 50,000 IU of urokinase precursor, 40 mg of human albumin and 12.8 mg of arginine.
  • Cultivated human kidney cells were grown for 3 days in a 0.1% human serum albumin-added non-serum culture, and the fermentation broth thus obtained was subjected to centrifugal separation. The resulting supernatant was frozen and stored. The pooled supernatant was adjusted to pH 5.5 and contacted with CM-Sephadex C-50. After washing a column with a 0.16 M phosphate buffer (pH 5.5), the adsorbed urokinase precursor was eluted with a 0.16 M phosphate buffer (pH, 8.5).
  • hybridomas prepared by fusion using polyethylene glycol of spleen cells of BALB/c mouse which had been immunized with the urokinase precursor and mouse myeloma cells a clone having a high productivity of antibody for the urokinase precursor was selected. From this fermentation broth of the fused cells, an anti- urokinase monoclonal antibody was recovered. This monoclonal antibody was immobilized on BrCN-activated Sepharose 4B (produced by Pharmacia Co., Ltd.)
  • This monoclonal antibody column was equilibrated with a 0.1 M phosphate buffer (pH, 7.0) containing 0.4 M NaCl, and then contacted with the eluate containing urokinase precursor. After washing the column with a 0.1 M phosphate buffer (pH, 7.-0) containing 0.4 M NaCl, the adsorbed urokinase precursor was eluted with a 0.2 M aqueous glycine-HCl solution (pH: 2.5) containing 0.5 M NaCl. The eluate was neutralized and then was passed through a carrier fixed anti-mouse IgG rabbit IgG and was removed a very small amount of exuded mouse IgG. The solution thus passed was freed from bacteria and filtered, and then freeze dried to obtain a highly purified urokinase precursor having a specific activity of at least 80,000 IU/mg.
  • This purified product when measured with SDS polyacrylamide gel electrophoresis, showed one band ascribable to a molecular weight of 50,000.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Microbiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP86105235A 1985-04-16 1986-04-16 Méthode de stabilisation d'un précurseur d'urokinase et préparation sèche contenant ce précurseur Expired - Lifetime EP0200966B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP60079428A JPS61238731A (ja) 1985-04-16 1985-04-16 ウロキナーゼ前駆体乾燥製剤
JP79429/85 1985-04-16
JP60079429A JPS61238732A (ja) 1985-04-16 1985-04-16 ウロキナーゼ前駆体乾燥製剤
JP79428/85 1985-04-16

Publications (3)

Publication Number Publication Date
EP0200966A2 true EP0200966A2 (fr) 1986-11-12
EP0200966A3 EP0200966A3 (en) 1988-09-28
EP0200966B1 EP0200966B1 (fr) 1993-07-21

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EP86105235A Expired - Lifetime EP0200966B1 (fr) 1985-04-16 1986-04-16 Méthode de stabilisation d'un précurseur d'urokinase et préparation sèche contenant ce précurseur

Country Status (5)

Country Link
EP (1) EP0200966B1 (fr)
KR (1) KR940003056B1 (fr)
CA (1) CA1336585C (fr)
DE (1) DE3688713T2 (fr)
ES (1) ES8706821A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190041A2 (fr) * 1985-01-30 1986-08-06 Green Cross Corporation Précurseur d'un activateur de plaminogène stabilisé et son procédé de préparation
EP0295940A2 (fr) * 1987-06-18 1988-12-21 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JCR PHARMACEUTICALS CO., LTD Méthode pour supprimer la dégradation thermique de l'urokinase
EP0380334A2 (fr) * 1989-01-27 1990-08-01 The Green Cross Corporation Composition à base d'un précurseur de l'urokinase et d'un lipide
EP0391400A2 (fr) * 1989-04-07 1990-10-10 The Green Cross Corporation Procédé de stabilisation du précurseur de l'urokinase et préparation desséchée
EP0395918A2 (fr) * 1989-04-13 1990-11-07 Vascular Laboratory, Inc. Complexe d'activateur de plasminogène de pro-urokinase pure liée de manière covalente par un pont disulfure à de la sérum albumine humaine

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9333280B2 (en) 2009-02-25 2016-05-10 Teleflex Medical Incorporated Stabilized enzyme compositions
US8545459B2 (en) 2009-02-25 2013-10-01 Teleflex Medical Incorporated Stabilized enzyme compositions
CA2925858A1 (fr) 2013-09-30 2015-04-02 Teleflex Medical Incorporated Compositions d'enzymes stabilisees

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2021412A (en) * 1978-05-12 1979-12-05 Sumitomo Chemical Co Method for preparing urokinase injection
US4245051A (en) * 1978-03-30 1981-01-13 Rockefeller University Human serum plasminogen activator
JPS58224687A (ja) * 1982-06-24 1983-12-27 Toubishi Yakuhin Kogyo Kk プラスミノ−ゲン活性化酵素剤及びその新規製造方法
JPS59139323A (ja) * 1983-01-28 1984-08-10 Green Cross Corp:The ウロキナ−ゼ乾燥製剤
EP0139447A2 (fr) * 1983-09-13 1985-05-02 The Green Cross Corporation Procéde pour la préparation du Zymogène d'urokinase
EP0151996A2 (fr) * 1984-01-30 1985-08-21 Asahi Kasei Kogyo Kabushiki Kaisha Procédé de préparation d'un activateur de plasminogène double-chaîne
EP0190041A2 (fr) * 1985-01-30 1986-08-06 Green Cross Corporation Précurseur d'un activateur de plaminogène stabilisé et son procédé de préparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4245051A (en) * 1978-03-30 1981-01-13 Rockefeller University Human serum plasminogen activator
GB2021412A (en) * 1978-05-12 1979-12-05 Sumitomo Chemical Co Method for preparing urokinase injection
JPS58224687A (ja) * 1982-06-24 1983-12-27 Toubishi Yakuhin Kogyo Kk プラスミノ−ゲン活性化酵素剤及びその新規製造方法
JPS59139323A (ja) * 1983-01-28 1984-08-10 Green Cross Corp:The ウロキナ−ゼ乾燥製剤
EP0139447A2 (fr) * 1983-09-13 1985-05-02 The Green Cross Corporation Procéde pour la préparation du Zymogène d'urokinase
EP0151996A2 (fr) * 1984-01-30 1985-08-21 Asahi Kasei Kogyo Kabushiki Kaisha Procédé de préparation d'un activateur de plasminogène double-chaîne
EP0190041A2 (fr) * 1985-01-30 1986-08-06 Green Cross Corporation Précurseur d'un activateur de plaminogène stabilisé et son procédé de préparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, vol. 8, no. 260 (C-254)[1697], 29th November 1984; & JP-A-59 139 323 (MIDORI JUJI K.K.) 10-08-1984 *
PATENT ABSTRACTS OF JAPAN, vol. 8, no. 71 (C-217)[1508], 3rd April 1984; & JP-A-58 224 687 (TOUBISHI YAKUHIN KOGYO K.K.) 27-12-1983 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190041A2 (fr) * 1985-01-30 1986-08-06 Green Cross Corporation Précurseur d'un activateur de plaminogène stabilisé et son procédé de préparation
EP0190041A3 (fr) * 1985-01-30 1988-09-28 Green Cross Corporation Précurseur d'un activateur de plaminogène stabilisé et son procédé de préparation
US5075230A (en) * 1985-01-30 1991-12-24 The Green Cross Corporation Stabilized plasminogen activator precursor and method of producing the same
EP0295940A2 (fr) * 1987-06-18 1988-12-21 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JCR PHARMACEUTICALS CO., LTD Méthode pour supprimer la dégradation thermique de l'urokinase
EP0295940A3 (en) * 1987-06-18 1989-05-31 Nihon Chemical Research Kabushiki Kaisha Also Known As Japan Chemical Research Co., Ltd Method of suppressing the thermal degradation of urokinase
US4946785A (en) * 1987-06-18 1990-08-07 Japan Chemical Research Co., Ltd. Method of suppressing the thermal degradation of urokinase
EP0380334A2 (fr) * 1989-01-27 1990-08-01 The Green Cross Corporation Composition à base d'un précurseur de l'urokinase et d'un lipide
EP0380334A3 (fr) * 1989-01-27 1991-10-09 The Green Cross Corporation Composition à base d'un précurseur de l'urokinase et d'un lipide
EP0391400A2 (fr) * 1989-04-07 1990-10-10 The Green Cross Corporation Procédé de stabilisation du précurseur de l'urokinase et préparation desséchée
EP0391400A3 (fr) * 1989-04-07 1990-11-14 The Green Cross Corporation Procédé de stabilisation du précurseur de l'urokinase et préparation desséchée
EP0395918A2 (fr) * 1989-04-13 1990-11-07 Vascular Laboratory, Inc. Complexe d'activateur de plasminogène de pro-urokinase pure liée de manière covalente par un pont disulfure à de la sérum albumine humaine
EP0395918A3 (fr) * 1989-04-13 1991-10-23 Vascular Laboratory, Inc. Complexe d'activateur de plasminogène de pro-urokinase pure liée de manière covalente par un pont disulfure à de la sérum albumine humaine

Also Published As

Publication number Publication date
ES554477A0 (es) 1987-07-01
DE3688713T2 (de) 1993-12-16
DE3688713D1 (de) 1993-08-26
EP0200966B1 (fr) 1993-07-21
EP0200966A3 (en) 1988-09-28
ES8706821A1 (es) 1987-07-01
KR940003056B1 (ko) 1994-04-13
KR860008199A (ko) 1986-11-12
CA1336585C (fr) 1995-08-08

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